recent advances in medical treatment of inflammatory

8/14/2019 Recent Advances in Medical Treatment of Inflammatory

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Nutritional treatment in IBD

Uses - Forimproving nutritional status - As primary therapy for active disease - For themaintenance of remission

Types- parenteral nutrition -elemental diets - polymeric diets

specific nutrients e.g. fish oil, glutamine- exclusion diets


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Parenteral nutrition

Improved disease activity and nutritional statusreported in several small uncontrolled studies

Multicentre prospective study Greenberg 1988

TPN alone, partial PN + normal food and a polymericdiet were equally effective

Concluded bowel rest not necessary and PN should besupportive, not primary therapy


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Parenteral nutrition

May help to achieve remission in patients withstrictures or short bowel syndrome

Perioperative PN results in less small bowelresection but longer hospitalisation

More complications with PN (esp sepsis)


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Elemental diets

Chemically defined liquid diets containing amino acidsimple carbohydrates, fats etc.

First RCT by OMorain 1984 suggested elemental dietwere as effective as steroids at inducing remission

Similar results and improved growth confirmed bySanderson 1987 in first paediatric RCT


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Enteral nutritional therapy for inducing

remission of Crohns diseaseZachos M, Tondeur M, Griffiths AM Cochrane Library 2001

Part A: Meta-analysis 9 RCTs comparing elemental diet

(n=170) to non-elemental diet (n=128) showed N.S.difference in remission rate [OR 1.15, 95% CI: 0.64-2.08

Part B: Meta-analysis 4 RCTs comparing enteral nutritio

(n=130) to steroids (n=123) showed steroids better at

inducing remission [OR 0.30, 95% CI: 0.17-0.52, NNT=4


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Enteral nutrition in growth failure

15-50% children with Crohns disease have growthfailure

Malnutrition probably most important cause

Macro/micronutrient deficiencies common

Inflammatory mediators and IGF-I

Improved growth with long-term oral supplements


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Supplementary enteral nutrition maintains remissioin pediatric Crohns disease

Wilschanski M et al, Gut 1996;38:543-8

Retrospective review of 65 children with active Crohndisease treated with enteral nutrition

47 (72%) achieved remission (PCDAI


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EN mechanism of action

improved nutritional status (macro/micro)

improved luminal nutrition

improved immune function

reduced antigenic load to gut

altered gut flora

reduced inflammatory mediator production


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Double-blind RCT of glutamine-enriched polymer

diet in the treatment of active Crohns diseaseAkobeng AK et al, J Pediatr Gastroenterol Nutr 2000;30:78-84

18 children with active Crohns received for 4/52 a glutaminerich (42% amino acids) or low glutamine (4% amino acids)

polymeric diet in DBRCT

Diets were isocaloric & isonitrogenous with iddentical essentiaamino acid profile

2 patients in high glutamine group did not tolerate the diet

N.S. diff. in remission rates [OR 0.64, 95% CI 0.10-4.11]


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Pharmacological treatment

Sulphasalazine/5-ASA Corticosteroids/budesonide

Antibiotics/antimycobacterial therapy

Azathioprine/6-mercaptopurine

Cyclosporine A

Methotrexate

Mycophenolate mofetil

Tacrolimus Anti-TNF agents: thalidomide, infliximab


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Oral 5-ASA for inducing remission in ulcerative

colitis. Sunderland L et al, Cochrane Review 1998 OR (95% CI) for failure to induce remission/improvement = 0.51

(0.36-0.76), dose response curve observed

Compared to sulphasalazine, OR (95% CI) for failure to induce

remission/improvement = 0.87 (0.63-1.21) & 0.66 (0.42-1.04) forfailure to induce endoscopic improvement

Sulphasalazine not as well tolerated as 5-ASA

5-ASA superior to placebo for all outcomes and tended towardsbenefit over sulphasalazine but benefits may not be economically

justifiable


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Oral 5-ASA for maintaining remission in ulcerative

colitis. Sutherland L et al, Cochrane Review 1998

OR (95% CI) for failure to maintain clinical or endoscopicremission for 5-ASA v placebo = 0.47 (0.36-0.62), NNT = 6

OR (95% CI) for failure to maintain clinical or endoscopic

remission for sulphasalazine v 5-ASA = 1.29 (1.05-1.57), NNT =-19 Sulphasalazine & 5-ASA had similar adverse event profiles, OR

(95% CI) = 1.16 (0.62-2.16) & 1.31 (0.86-1.99), NNH = 171 & 7 5-ASA superior to placebo but inferior to sulphasalazine in

maintenance therapy


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Corticosteroids for maintaining remission of Crohn

disease.Steinhart AH et al, Cochrane Review 2001

3 eligible studies identified

No. of subjects included at 6, 12 & 24 months = 142,

131 & 95 for steroid group & 161,138 & 87 for control group

OR (95% CI) for relapse = 0.71 (0.39-1.31) at 6/12,0.82 (0.47-1.43) at 12/12 & 0.72 (0.38-1.35) at 24/12

The use of corticosteroids in patients with quiescentCrohns disease does not appear to reduce the risk ofrelapse over a 24 month period of follow-up


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Budesonide

Potency 15x that of prednisolone

Delayed release capsule facilitates delivery to terminal

ileum and proximal colon

Rapid liver metabolism means only 10% bioavailability cf80% for prednisolone

Efficacy comparable to prednisolone with fewer side

effects in adults with ileocaecal Crohns

Multinational paediatric study completed


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Budesonide for maintenance of

remission in Crohns diseaseSimms L, Steinhart AH Cochrane Review 2000

3 RCTs of oral budesonide 6mg/day, 3 mg/day and

placebo

Budesonide 6mg/day ineffective at preventing relapse

over 12 months. RR relapse = 0.89 (95% CI: 0.71-1.13)

Similar results with 3mg/day


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Topical agents

5-ASA enemas

Low systemic absorption

In DBRCT 63% much improved after 6/52 cf. 29% in

placebo gp.

No proven benefit of 4g cf. 1g

May be more effective than hydrocortisone

High relapse rate after cessation No data in L. sided Crohns colitis


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Topical agents continued

Corticosteroid enemas

Hydrocortisone & prednisolone based preparations activeafter absorption, risk of systemic side effects

Beclomethasone, fluticasone & budesonide have rapid 1stpass hepatic metabolism & low systemic bioavailability aftrectal administration

Budesonide enemas probably have highest topical potencywith lowest risk of side effects


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Rectal corticosteroids versus alternative treatments

ulcerative colitis: a meta-analysisMarshall JK et al, Gut 1997;40:775-81

56 RCTs identified = 4288 patients

Conventional rectal steroids, remission rates: symptomati45%, endoscopic 34%, histological 30%

Topically active steroids, remission rates: symptomat46%, endoscopic 31%, histological 23%

Aminosalicylates, remission rates:symptomatic 52%, endoscopic 39%, histological 32%

Placebo, remission rates:symptomatic 9%, endoscopic 17%


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Anti-tuberculous therapy for Crohns diseaseBorgaonkar MR et al, Cochrane Library 1999

7 RCTs identified (2 abstracts)

2 trials (n=89) used ATT + steroids to induce remission thenmaintenance ATT, OR for maintaining remission in ATT v cont= 3.37 (95% CI 1.38-8.24, NNT=3)

3 trials used ATT + standard therapy v standard therapy alone, Ofor maintaining remission in treatment v control = 0.70 (95% CI0.39-1.25)

ATT may be effective in maintaining remission induced with

steroids + ATT but cannot be recommended as conclusion basedon only 2 small studies


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Azathioprine or 6-Mercaptopurine for

inducing remission of Crohns disease

Sandborn W et al, Cochrane Review 1998

8 placebo controlled RCTs identified

OR (95% CI) of response to AZA / 6-MP in active CD = 2.36(1.57-3.53), NNT = 5, OR (95% CI) for steroid sparing effect =

3.86 (2.14-6.96), NNT = 3

OR (95% CI) for adverse event (allergy, leukopenia, pancreatitisnausea) = 3.01 (1.30-6.96), NNH = 14

Azathioprine & 6-MP are effective at inducing remission in activ

Crohns disease. Treatment >17/52 improved response


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Azathioprine for maintenance of remission in Crohn

disease. Pearson DC et al, Cochrane Review 1998

5 placebo controlled DBRCTs identified

OR (95% CI) for maintenance of remission = 2.16 (1.4-3.5), NNT =

Higher dose improved response (OR = 1.2 at 1mg/kg/day, 3. 2 at

2mg/kg/day & 4.1 at 2.5mg/kg/day)

OR for steroid sparing effect = 5.22 (1.1-25.7), NNT = 3

OR for withdrawal due to adverse events = 4.36 (1.6-11.7),

NNH = 19


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A multicenter trial of 6-MP & prednisone in childre

with newly diagnosed Crohns diseaseMarkowitz J et al, Gastroenterology 2000;119:895-902

55 newly diagnosed Crohns children randomised to

prednisone & 6-MP or placebo for 18 months

Prednisone dose tailored to disease activity according topredefined schedule

Remission in 89% of both groups, relapse rate 47% in

controls & 9% in 6-MP group

In 6-MP group duration of steroid use shorter and cumulativdose lower at 6, 12 & 18 months


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Topical tacrolimus may be effective in the treatment

oral and perineal Crohns disease

Casson DH et al, Gut 2000;47:436-40.

Topical tacrolimus given to 8 children with refractory oral (3)&/or perineal (6) Crohns

Marked improvement in 7/8 within 6 wks & healing in 1-6months, undetectable serum levels

2/7 rebound worsening when tacrolimus stopped & 1 requiredproctocolectomy

Slower weaning successful in 6/8 with 4 on intermittenttreatment & 2 on reduced dosage


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TNF

Potent proinflammatory cytokine

Can elicit fever, shock, tissue injury, induction of

other cytokines, cell proliferation, differentiation &

apoptosis (Papadikas 2000)

In Crohns disease production increased in GI mucosa

(Reimund 1996, MacDonald 1990, Breese 1994) and

serum concentrations increased (Murch 1991).


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Infliximab

Neutralises TNF effects (in vitro & in vivo) by blocking soluble TNFbinding to trans-membrane TNF (Siegel 1995, Scallon 1995)

Several studies have shown clinical or endoscopic benefits in adults with

fistulising or refractory Crohns disease (Targan 1997, Baert 1999,Rutgeerts 1999) but studies are small & limited paediatric data


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Remicade - safety alert January 2002

~200,000 patients have received Remicade since

1st licensed in 1998

Commonest serious adverse effect is infection. By

mid 2001 130 cases of TB and 202 deaths reported

Other safety concerns include heart failure,

hypersensitivity reactions, neurological events &

malignancies


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Remicade - safety alert January 2002

Indications for treatment of Crohns disease

Severe, active Crohns disease in patients who have not respondeddespite a full and adequate course of therapy with a corticosteroidan immuno-suppressant; or who are intolerant to or havecontraindications for such treatment

Fistulising Crohns disease, in patients who have not respondeddespite a full & adequate course of conventional treatment includiantibiotics, drainage & immunosuppressives


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National Institute for Clinical Excellence (NICE

Guidelines I (April 2002)

Patients must fulfil all three criteria:

Severe active Crohns disease (CDAI 300+,Harvey-Bradshaw 8/9+)

Refractory to immunomodulators & steroids orintolerant of these

Surgery is inappropriate (e.g. because of diffusedisease &/or risk of short bowel syndrome)


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NICE Guidelines II (April 2002)

Treatment can be repeated if respond to initialcourse then relapse (episodic treatment)Infliximab not licensed for maintenance treatment(repeated dosing each 8 weeks)Cost per QALY:

6,700 for single infusion

10,400 for episodic treatment 84,400 for maintenance treatment

Not recommended for fistulising disease withoutother criteria for severe active Crohns

Maintenance infliximab for Crohns disease:


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Maintenance infliximab for Crohns disease:

the ACCENT I randomised trial Hanauer SB et al.Lancet 2002;359;1541-1549

573 adults with CDAI 220+ given 5mg/kg infliximab

335 responders randomised to receive: placebo (gp ) I

5mg/kg (gp II), 10mg/kg (gp III) 8 weekly to week 46

Wk 30: remission in 21% gp I, 39% gp II, 45% gp III

Median time to loss response: 19 weeks gp I, 38 weeks

gp II, >54 weeks gp III

Incidence serious infections similar across groups


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BSPGHAN survey

Audit proposed by BSPGHAN IBD workinggroup

BSPGHAN members notified at AGM & vianewsletters

Aims: to identify benefits & side-effects in UKchildren with Crohns disease


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Methods

Data collected:

extent of disease

indication for using infliximab

number of doses & total dose given

other treatments

outcome including side effects

Data collected on forms and sent to coordinator


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Results

45 children (aged 0.3 - 17yr, median 12yr) reported

Indications for treatment included:

severe unresponsive disease 33

perianal fistulae 18

other fistulae 7

steroid dependence 7


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Results continued

Most children received dosages of 5 (range 3-10) mg/kg

The median number of doses received was 3 (range 1-6)

6 children are receiving maintenance treatment (8 weekly

infusions)


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Results continued

in 3 children there was no reported improvement afterinfliximab

improvement of fistulae was reported in 16

improvement in perianal disease in 15

avoidance of surgery in 12

reduced need for other drugs in 18

improvement in symptoms/quality of life in 35


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Results continued

The median duration of response was 4.5 months(range 1 week to >20 months)

Reported side effects included:anaphylactic reaction (1) (with 3rd dose)hepatitis (1)fever (2)lupus like reaction (1)

candidal endophthalmitis (1)worse after initial improvement (1)


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Results continued

12 of 15 patients with severe unresponsive disease aloneappear to have fulfilled recommendations followingsafety alert

1 of these patients didnt receive steroids, 1 didnt receivimmunomodulators and 1 didnt receive either beforeinfliximab


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Results continued

22 of 24 patients with fistulae improved but only 4

completely fulfilled the manufacturers

recommendations, most had not had drainage of

fistulae and many appeared to have not receivedantibiotics

10 of the 24 with fistulae did not have other criteria

for severe active disease but improvement reported

in all 10


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Conclusions

Infliximab appears to be beneficial in many patients withfistulising or refractory Crohns disease

There is increasing concern in adults about serious adverse effectespecially infections

Although infliximab is being widely used there are limited dataespecially in children

This audit raises questions over relevance of manufacturers andNICE recommendations

Data from adequately powered RCTs needed to answer these

questions


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Summary I: Nutritional Treatment

Bowel rest unnecessary, parenteral nutrition should be

supportive

Steroids are significantly better than enteral nutrition atinducing remission in active Crohns disease

Enteral nutrition promotes growth & may help to prolong

remission

Glutamine of no proven benefit in active Crohns disease


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Summary II: 5-ASA & steroids

5-ASA has less side effects than sulphasalazine & of

benefit in treatment & maintenance of UC & Crohns

Rectal 5-ASA better than steroids in distal UC

Corticosteroids effective in ileal & ileocolic Crohns,

isolated colonic Crohns benefits from adding 5-ASA

Steroids do not prevent relapse


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Summary III: Anti TNF agents

Infliximab of short-term benefit in fistulising & severe

Crohns (refractory or intolerant to immunosuppressives)

Additional doses may be necessary but little data about

long-term effects or side effects

recent advances in medical treatment of inflammatory

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